Genetics of Bone and Vascular Calcium in Type 2 Diabetes

描述(由申请人提供)： 广泛的长期目标是改善健康和减少死亡。 患有骨质疏松症、心血管疾病和2型糖尿病的人。具体目标是 重点关注导致血管病变的遗传和环境因素 2型糖尿病家系中的钙化(VC)和骨矿化(BM)。 与健康相关的是心血管疾病(CVD)是第一位的 美国的死因和心血管疾病的风险显著增加 2型糖尿病患者。1000万人中存在骨质疏松症 另有1800万人估计骨量偏低。这是一个 对《2型亚临床脑血管病的遗传流行病学》的补充建议 糖尿病“(HL67348)也称为”糖尿病心脏研究“或DHS。DHS使用 心血管疾病表型定位的家系研究设计及定量测量 并确定导致兄弟姐妹亚临床动脉粥样硬化的基因 对于2型糖尿病，配对是一致的。生活方式和环境的影响 关于BM和VC测量的亚临床疾病的基因表达 下定决心。在这项建议中，骨矿化和主动脉腔静脉的测量 将被添加到我们现有的CVD表型阵列中，其中包括血管 冠状动脉和颈动脉的钙(Vc)。我们将使用额外的 BM的定量测量(QCT、DXA、QS和生物标志物)以了解 BM、VC、CVD、骨质疏松与2型糖尿病的遗传关系 具体目标是：1)在高风险环境下对BM和VC进行度量和描述 心血管疾病的人群，兄弟姐妹对患有2型糖尿病的家庭 以及未受影响的家庭成员。2)测量两者之间的关联强度 血管钙和骨矿化-进一步表征 通过2型糖尿病的存在或不存在、种族和性别进行关联。 3)估计BM和VC的家族聚集度和遗传度 糖尿病心脏研究家族。4)调查候选基因多态， 以前确定的BM和VC与主要表型相关 以国土安全部衡量。5)确定包含以下内容的特定染色体区域 影响BM和VC的数量性状基因座(QTL) 屏幕上。6)进行精细作图，进行关联和单倍型分析， 并为染色体区域寻找新的候选基因 与主要表型BM、VC和CVD相关联的证据。一个老牌的 和积极的多学科调查团队，使用先进的方法 表型量化、分子遗传学和遗传流行病学将 进行这项研究。

DESCRIPTION (provided by applicant): The broad long-term objectives are to improve health and reduce deaths in people from osteoporosis, CVD and type 2 diabetes. The specific aims are focused on the genetic and environmental factors that contribute to vascular calcification (VC) and bone mineralization (BM) in type 2 diabetic families. The health relatedness is that cardiovascular disease (CVD) is the number one cause of death in the U.S. and the risk of CVD is significantly increased in individuals with type 2 diabetes. Osteoporosis is present in 10 million citizens with another 18 million estimated to have low bone mass. This is an ancillary proposal to the "Genetic Epidemiology of Subclinical CVD in Type 2 Diabetes" (HL67348) also know as the "Diabetes Heart Study" or DHS. DHS uses a family study design and quantitative measurement of CVD phenotypes to locate and identify genes contributing to subclinical atherosclerosis in sibling pairs concordant for type 2 diabetes. The impact of lifestyle and environment on gene expression for subclinical disease as measured by BM and VC will be determined. In this proposal, measures of bone mineralization and aortic VC will be added to our existing array of CVD phenotypes, which include vascular calcium (VC) of the coronary and carotid arteries. We will use the additional quantitative measures of BM (QCT, DXA, QUS & Biomarkers) to understand the genetic relation between BM, VC, CVD, osteoporosis and type 2 diabetes. The Specific Aims are: 1) Measure and describe BM & VC in a high-risk population for CVD, families with sibling pairs concordant for type 2 diabetes and unaffected family members. 2) Measure the strength of association between vascular calcium and bone mineralization - further characterize the association by presence or absence of type 2 diabetes, ethnicity, and gender. 3) Estimate the familial aggregation and heritability of BM & VC in the Diabetes Heart Study families.4) Investigate if candidate gene polymorphisms, previously identified for BM & VC, are associated with the primary phenotypes measured in DHS. 5) Identify specific chromosomal regions containing quantitative trait loci (QTLs), which influence BM &VC, using the genome-wide screen. 6) Perform fine mapping, conduct association and haplotype analyses, and identify novel candidate genes for chromosomal regions with strong evidence for linkage to the primary phenotypes, BM, VC and CVD. An established and active multidisciplinary team of investigators using advanced methods of phenotype quantification, molecular genetics, and genetic epidemiology will conduct this research.